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Medical Journal Review

April 2022

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Treatment patterns and frequency of key outcomes in acute severe asthma in children: A Paediatric Research in Emergency Departments International Collaborative (PREDICT) multicentre cohort study
Craig S, Powell CVE, Nixon GM, Oakley E, Hort J et al
BMJ Open Respiratory Research 2022;9(1):e001137 (17 March)

In this large retrospective cohort study of over 14,000 children with an emergency department diagnosis of asthma or wheeze in Australian and New Zealand hospitals, the authors examined the use and type of escalation of treatment. They found in those with escalation of treatment required a longer LOS (44.2 hours, IQR 27.3–63.2 hours) than children without escalation 6.7 hours, IQR 3.5–16.3 hours; p<0.001). The most common treatment escalations were respiratory support alone (400; 2.9%, 95% CI 2.6% to 3.1%), parenteral bronchodilator treatment alone (380; 2.7%, 95% CI 2.5% to 3.0%), and both respiratory support and parenteral bronchodilator treatment (209; 1.5%, 95% CI 1.3% to 1.7%). Respiratory support was predominantly nasal high-flow therapy (99.0%). The most common intravenous medication regimens were: magnesium alone (50.4%), magnesium and aminophylline (24.6%), and magnesium and salbutamol (10.0%). Overall, they found a wide variation in both the frequency and nature of escalation of treatment for children with emergency department presentations for acute severe asthma.

Strategies for using topical corticosteroids in children and adults with eczema
Lax SJ, Harvey J, Axon E, Howells L, Santer M et al
Cochrane Database of Systematic Reviews 2022; 11:3:CD013356 (11 March)

While topical corticosteroids have been a first-line treatment for eczema for decades, there are uncertainties over their optimal use. Thus, the objective of this Cochrane analysis was to establish the effectiveness and safety of different ways of using topical corticosteroids for treating eczema. Through this analysis the authors found that potent and moderate topical corticosteroids are probably more effective than mild topical corticosteroids, primarily in moderate or severe eczema; however, it should be noted that there is uncertain evidence to support any advantage of very potent over potent topical corticosteroids. Furthermore, effectiveness is similar between once daily and twice daily (or more) frequent use of potent topical corticosteroids to treat eczema flare-ups, and topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare-ups). The authors found that adverse events were not well reported and came largely from low- or very low-certainty, short-term trials. In trials that reported abnormal skin thinning, frequency was low overall and increased with increasing potency. The authors found no trials on the optimum duration of treatment of a flare, branded versus generic topical corticosteroids, and time to leave between application of topical corticosteroids and emollient. They conclude by noting that there is a need for longer-term trials in people with mild eczema.

Bradykinin-induced angioedema in the emergency department
Hébert J, Boursiquot JN, Chapdelaine H, Laramée B, Desjardins M et al
International Journal of Emergency Medicine 2022;15:15 (26 March)

It is well known that poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of several treatment options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. In this article the authors present a systematic literature review exploring the effectiveness of the available therapies for managing such cases and explore differences in bradykinin versus histamine-induced angioedema. In contrast to bradykinin-induced angioedema, histamine-induced angioedema is faster in onset and often presents with urticaria. The authors highlight that acute airway angioedema in the ED should initially be treated with anaphylactic protocols (if physiology of angioedema is unknown), focusing on airway management and treatment with epinephrine, antihistamine, and systemic steroids. Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade.

Predicting the course of asthma from childhood until early adulthood
Koefoed HJL, Vonk JM, Koppelman GH
Current Opinion in Allergy and Clinical Immunology 2022;22(2):115-112 (1 April)

This review highlights recent insights regarding the natural history of childhood asthma, with a focus on prediction of persistence and remission of childhood asthma, up to early adulthood. Studies demonstrate that lung function around the age of 8–9 years is the strongest predictor: obstructive lung function predicts asthma persistence up to early adulthood, whereas normal lung function predicts remission. Furthermore, the ability to predict asthma remission improves when lung function is combined with blood eosinophil levels and degree of bronchial hyperresponsiveness. Interventions, such as inhaled corticosteroids and immunotherapy do not appear to alter the course of asthma. Epigenetic studies have revealed potential novel biomarkers of asthma remission, such as micro-RNA patterns in blood. Specifically, lower serum levels of mi-R221-5p, which is associated with lower IL-6 release and eosinophilic inflammation, predict remission, while levels of blood DNA-methylation of a CpG site in Peroxisomal Biogenesis Factor 11 Beta appear to be associated with asthma remission.

SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13
Morrison CB, Edwards CE, Shaffer KM, Ehre C
Proceedings of the National Academy of Sciences 2022;119(16):e2119680119 (19 April)

Muco-obstructive lung diseases are typically associated with high risks of COVID-19 severity; except in the case of allergic asthma, where there appears to be reduced susceptibility. To investigate viral spread, primary human airway epithelial (HAE) cell cultures were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Host–virus interactions were examined via electron microscopy, immunohistochemistry, RNA in situ hybridization, and gene expression analyses. In HAE cell cultures, angiotensin-converting enzyme 2 (ACE2) expression governed cell tropism and viral load and was up-regulated by infection. Electron microscopy identified intense viral egress from infected ciliated cells and severe cytopathogenesis, culminating in the shedding of ciliated cells packed with virions, providing a large viral reservoir for spread and transmission. Intracellular stores of MUC5AC, a major airway mucin involved in asthma, were rapidly depleted, likely to trap viruses. To mimic asthmatic airways, HAE cells were treated with interleukin-13 (IL-13), which resulted in reduction in titers, viral messenger RNA, and cell shedding, and significantly diminished the number of infected cells. Although mucus hyper-production played a shielding role, IL-13–treated cells maintained a degree of protection despite the removal of mucus. Using Gene Expression Omnibus databases, bulk RNA-sequencing analyses revealed that IL-13 up-regulated genes controlling glycoprotein synthesis, ion transport, and antiviral processes (albeit not the typical interferon-induced genes) and down-regulated genes involved in cilial function and ribosomal processing. More precisely, we showed that IL-13 reduced ACE2 expression, intracellular viral load, and cell-to-cell transmission while increasing the cilial keratan sulfate coating. In conclusion, intense viral and cell shedding caused by SARS-CoV-2 infection was attenuated by IL-13, which affected viral entry, replication, and spread.

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